TY - JOUR
T1 - Inducible Depletion of Calpain-2 Mitigates Abdominal Aortic Aneurysm in Mice
AU - Muniappan, Latha
AU - Okuyama, Michihiro
AU - Javidan, Aida
AU - Thiagarajan, Devi
AU - Jiang, Weihua
AU - Moorleghen, Jessica J.
AU - Yang, Lihua
AU - Balakrishnan, Anju
AU - Howatt, Deborah A.
AU - Uchida, Haruhito A.
AU - Saido, Takaomi C.
AU - Subramanian, Venkateswaran
N1 - Publisher Copyright:
© 2021 American Heart Association, Inc.
PY - 2021/5/5
Y1 - 2021/5/5
N2 - Objective: Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix with contractile filaments. During abdominal aortic aneurysm (AAA) development, (1) aortic medial degeneration is associated with loss of smooth muscle cell integrity and (2) fibrogenic mesenchymal cells mediate extracellular matrix remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Ang II (angiotensin II)-induced AAAs in LDLR-/- (low-density receptor deficient) mice. Here, we evaluated the functional contribution of fibrogenic mesenchymal cells-derived calpain-2 on (1) cytoskeletal structural protein and extracellular matrix alterations and (2) AAA progression. Approach and Results: Calpain-2 protein and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and Ang II-induced AAAs in mice. To examine the relative contribution of calpain-2 in AAA development, calpain-2 floxed mice in an LDLR-/- background were bred to mice with a tamoxifen-inducible form of Cre under control of either the ubiquitous promoter, chicken β-actin, or fibrogenic mesenchymal cell-specific promoter, Col1α2 (collagen type 1 alpha 2). Ubiquitous or fibrogenic mesenchymal cell-specific depletion of calpain-2 in mice suppressed Ang II-induced AAAs, filamin/talin fragmentation, while promoting extracellular matrix protein, collagen in the aortas. Calpain-2 silencing in aortic smooth muscle cells or fibroblasts reduced Ang II-induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established Ang II-induced AAAs in mice. Conclusions: Our studies implicate that calpain-2 deficiency prevents (1) Ang II-induced cytoskeletal structural protein fragmentation and AAA development and (2) stabilize and suppress rupture of established AAAs in mice.
AB - Objective: Cytoskeletal structural proteins maintain cell structural integrity by bridging extracellular matrix with contractile filaments. During abdominal aortic aneurysm (AAA) development, (1) aortic medial degeneration is associated with loss of smooth muscle cell integrity and (2) fibrogenic mesenchymal cells mediate extracellular matrix remodeling. Calpains cleave cytoskeletal proteins that maintain cell structural integrity. Pharmacological inhibition of calpains exert beneficial effects on Ang II (angiotensin II)-induced AAAs in LDLR-/- (low-density receptor deficient) mice. Here, we evaluated the functional contribution of fibrogenic mesenchymal cells-derived calpain-2 on (1) cytoskeletal structural protein and extracellular matrix alterations and (2) AAA progression. Approach and Results: Calpain-2 protein and cytoskeletal protein (filamin and talin) fragmentation are significantly elevated in human and Ang II-induced AAAs in mice. To examine the relative contribution of calpain-2 in AAA development, calpain-2 floxed mice in an LDLR-/- background were bred to mice with a tamoxifen-inducible form of Cre under control of either the ubiquitous promoter, chicken β-actin, or fibrogenic mesenchymal cell-specific promoter, Col1α2 (collagen type 1 alpha 2). Ubiquitous or fibrogenic mesenchymal cell-specific depletion of calpain-2 in mice suppressed Ang II-induced AAAs, filamin/talin fragmentation, while promoting extracellular matrix protein, collagen in the aortas. Calpain-2 silencing in aortic smooth muscle cells or fibroblasts reduced Ang II-induced filamin fragmentation. In addition, silencing of filamin in aortic SMCs significantly reduced collagen protein. Furthermore, calpain-2 deficiency suppressed rupture of established Ang II-induced AAAs in mice. Conclusions: Our studies implicate that calpain-2 deficiency prevents (1) Ang II-induced cytoskeletal structural protein fragmentation and AAA development and (2) stabilize and suppress rupture of established AAAs in mice.
KW - angiotensin II
KW - calpain
KW - cytoskeletal protein
KW - filamin A
KW - tamoxifen
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UR - http://www.scopus.com/inward/citedby.url?scp=85104745917&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.120.315546
DO - 10.1161/ATVBAHA.120.315546
M3 - Article
C2 - 33761765
AN - SCOPUS:85104745917
SN - 1079-5642
VL - 41
SP - 1694
EP - 1709
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -